N-cycloalkyl-n&#39;-cyanoalkyl alkoxybenzamides

ABSTRACT

SIMULTANEOUSLY ACTING CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS AND BLOOD PRESSURE DEPRESSORS OF THE FORMULA (A,B,C-PHENYL)-CO-N(-R)-(CH2)X-CN   WHEREIN A, B, AND C ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKOXY, AND HALOGEN RADICALS AT LEAST ONE OF WHICH IS AN ALKOXY OR A HALOGEN RADICAL; WHEREIN X IS A WHOLE NUMBER FROM ONE TO THREE, AND WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF CYCLOALIPHATIC RADICALS CONTAINING BETWEEN THREE AND SEVEN CARBON ATOMS.

United States Patent 3,660,461 N-CYCLOALKYL-N-CYANOALKYLALKOXYBENZAMIDES William D. Roll, Toledo, Ohio, assignor to The PatentedMay 2, 1972 ice amide. The cyanoalkyl radical of the benzamide maycomprise a cyano-methy1-, ethyl-, or propyl-radical, but preferably thecyanoethyl-radical, while the R radical may comprise a tri-, quatra-,penta-, hexa-, or hepta- University of Toledo, Toledo, Ohio 5cycloaliphatic radical, preferably the cyclohexyl radical, N0 DrawingFiled y 1969, 322,029 which together with the haloor methoxy-radicals onthe I Illt- A61k 27/00; 121/78 phenyl ring of the benzamide confers theproper physico- CL 260-465 D 5 Clams chemical properties on thesecompounds which are necessary for maximal activity in the animalstested. Al- 10 though the N-cyanoethyl-radical is preferred, the N-ABSTRACT OF THE DISCLOSURE cyanopropyl-radical also is good, but theN-cyanomethyl Simultaneously acting central nervous system (CNS) is lesseffective, and those N-cyanoalkyl radicals of four depressants and bloodpressure depressors of the formula or more carbon atoms produce nosignificant depressant A action in any practical dosages. B E N/(CHQFCN(B) Their preparation Q The new compounds according to this inventionwere 0 R prepared by the modification of the Schotten-Baumann wherein A,B, and C are selected from the group consist- Reaction according to thfollowing equation: ing of hydrogen, lower alkyl, lower alkoxy, andhalogen 2O CHZCH radicals at least one of which is an alkoxy or ahalogen 2 radical; wherein x is a whole number from one to three, C061 Nand wherein R is selected from the group consisting of E 1tcycloaliphatic radicals containing between three and seven New carbonatoms. 5

0 CHZCHZCN BACKGROUND OF THE INVENTION 2 Although similar N-cyanoalkylbenzamides are known, 6 N no similar ones were found which had either,not to mention both, the CNS depressant and blood pressure depressoreffects of applicants new compounds. For example; the Pursglove patentedHerein an acyl halide was reacted with an N-(2-cyano- 1960 is for abloclde the Saxon alklyl)-cycloalkylamine in the presence of sodiumhypaierited 1965 Is for E plastlclzer' droxide and chloroform at roomtemperature and agitated Although similar N-cycloalkyl benzamides areknown, until the exothermic reaction was complete. The chlorothey onlyhad biocide or CNS depressant effects, and none form layer was thenwashed with Water, dried with were blood pressure depressors hydroussodium sulfate and evaporated in a vacuum to furthermore. noN'cycloalkyl'N 'cyanoalkyl produce a viscous yellow oil whichcrystallized on standstltuted benzamldes have been found 40 ing for aperiod of several weeks. This crude product was SUMMARY OF THE INVENTIONthen re-crystallized from aqueous ethanol to give the pure (A) Thecompounds new compounds of this invention, which were tested forcomposition and physical properties. The results of some The newcompounds of this invention have central of these tests on the preferredN-cyclohexyl-N-cyanoethnervous system activity, stimulation ordepression in small yl-methoxyand chlorobenzamides are shown in thefolanimals such as rats and mice, depending upon the dosage lowing TableI:

TABLE I Phenyl Percent Ultra ring eld violet Infrared Calculated,Analyzed, substiby Melting data absorption percent percent tuted abovepoint Example No. radical process in C. A, m 6 =0 ON C H C H p-CHaO-76.8 77-78 282 1,679 1,630 2,265 71.30 7.74 71.33 7.78 2 m-CHaO- 75.0282 2,040 1,630 2,265 71.30 7. 74 71.77 7.83 3... O-CHaO- 74.5 43-44 2822,611 1,630 2,265 71.30 7.74 71.45 7.80 4 p-Cl- 79.4 93-64 266 1, 5001,630 2,265 56.08 6. 48 56.20 6.50 5 m-Cl 75.0 48-49 266 757 1,680 2,26566.08 6.58 66.12 6.53 6 o-Ol 78.4 56-57 266 391 1,630 2,255 66.08 6. 5855.14 6.50

(2 to 4 mg./kg.), and when they act as depressants in their largerdosages, they also produce a drop in blood pressure in these animals.

These new compounds have the general formula:

A B 0 CH2) CN (C) Their pharmacology The activity of these new compoundswas tested by dissolving them in propylene glycol and injecting theirresulting solutions into small animals such as rats and mice in dosagesof two and of four milligrams per kilogram of weight of the animalinjected. The depressant or stimulatory effects of the new compoundswere determined in mice with actophotometers which measure the totalmovements of a single animal each thirty minute interval over a two hourperiod and the mean count for each period for twelve animals for eachcompound was recorded. The direct blood pressure measurements for thesenew compounds were conducted in eight Wistar rats for each compound,which rats were under urethan anes- TABLE H [Al dosage 4 mgxlkg. inmice] Relative depressor action on-- Central nervous Compound ofsystem(CNS) Blood pressure Example number:

I I l I I I TABLE III [At dosage 2 mg./kg. in mice] Relative stimulationof central nervous system (CNS) Compound of- Example number:

+,++++-l-. 3... (Depressor 4 5 (Stimulation then depression.) 6(Depressor.)

DETAILED DESCRIPTION OF SOME PRE- FERRED EMBODIMENTS Example 1 Ncyclohexyl-N-cyanoethyl-p-methoxybenzamide was prepared by shaking amixture of milliliters of chloroform, 0.01 mole of N-(Z-cyanoethyl)cyclohexylamine, 60 milliliters of 5% sodium hydroxide, and 0.01 mole ofp-chloro-acyl chloride in a separator at room temperature until theexothermic action was complete. The chloroform layer was washed withwater, dried with anhydrous sodium sulfate, and evaporated in a vacuumto produce a viscous yellow oil which crystallized on standing for aperiod of several weeks. These crude crystals were then re-crystallizedfrom aqueous ethanol to form the pureN-cyclohexyl-N-cyanoethyl-pmethoxybenzamide sample of this example.

This sample was then tested according to the Table I above in which thecarbon and hydrogen content or percentages were obtained with a Colemancarbon-hydrogen analyzer. The melting point was determined by using aMettler FP-l melting and boiling point apparatus. The infraredabsorption spectra were obtained with a Perkin- Elmer Model 137-Bspectrophotometer, and the ultra violet data were obtained with a Bauschand Lomb Spectronic 600 Spectrophotometer.

The oral administration of four milligrams per kilogram of this Example1 compound dissolved in propylene glycol resulted in a significantreduction in the spontaneous motor activity of the mice and rats as wellas causing a simultaneous drop in blood pressure (see Table II above).Ataxia was clearly discernible in the animal at elevated dosages suchfor example ten milligrams per kilogram, and a rat responded even moredramatically to such elevated dosages, by assuming a cataleptoidposture. Slightly lower dosages on the other hand, say of two milligramsper kilogram of this new Example 1 compound, produced excitation in mice(see Table 1H above), and rather effectively. antagonized thetranquilizing activity of orally simultaneously administered 0.4milligram doses of perphenazine. This new compound also produced asignificant hypotensive effect when administered intraperitoneally tounanesthetized normotensive rats.

Example 2 N-cyclohexyl-N-cyanoethyl-m-methoxybenzamide was prepared fromm-methoxy acyl chloride and N-(Z-cyanoethyl) cyclohexylamine in the samemanner as that employed in Example 1 above, except that it was purifiedby chromatography on silica gel and eluted with petroleum ether, insteadof being recrystallized for its purification. The resulting compound wasalso tested as described in Example 1 above, and as shown in Tables I,H, and III above, to act in doses of 4 mg./kg. both as a CNS depressantand a blood pressure depressor.

Example 3 N cyclohexyl-N-cyanoethyl-o-methoxybenzamide also was producedin the manner described in Example 1 above and similarly tested asdescribed therein and as shown in the above Tables I, II, and HI, andwas shown to have both CNS depressant and blood pressure depressoractivity in dosages of 4 mg./kg.

Example 4 N-cyclohexyl-N-cyanoethyl-p-chlorobenzamide was also producedaccording to the process described for Example 1 above and similarlytested as shown in Table I.

Oral doses of this compound of two milligrams per kilogram in propyleneglycol produced a high degree of excitation but its antagonism to 0.4milligram per kilogram doses of perphenazine was insignificant. Althoughdepression was the predominant symptom of animals receiving doses offour milligram per kilogram of this new compound of Example 4, thedegree of reduction in spontaneous motor activity was less than that forthe compound of Example 1. It also was a blood pressure depressor asshown in Table II above.

Example 5 N-cyclohexyl-N-cyanoethyl m chlorobenzamide was also producedsimilar to the process described in Example 1, and it hadpharmacological effects similar to those for the compound of Example 2as shown in Table II. However, in smaller dosages, as shown in TableIII, it caused excitation during the first hour of measurement, but thespontaneous activity of mice receiving this reduced dosage rapidlydecreased during the next one and a half hour period.

Example 6 N-cyclohexyl-N-cyanoethyl o chlorobenzamide was producedaccording to the process described for Example 1 and was tested to haveproperties and an activity slightly less than the compound of Example 3.

I claim:

1. A compound of the formula 6 wherein A is selected from the groupconsisting of para References Cited and meta methoxy and ethoxyradicals, wherein x is 21 UNITED STATES PATENTS whole number from one toth ree, and wherein R is se- 2,927,126 3/1960 pursglove 260465 lectedfrom the group conslsting of cyclopropyl, cyclo- 3,457,294 7 /1969crovgtti et aL 5 butyl, cyclopentyl, cyclohexyl, and cycloheptylradicals. 5

2. A compound according to claim 1 wherein x is 2. JOSEPH REBOLD,Primary Examiner 3. A compound according to claim 1 wherein said R 1) HTQRRENCE, Assistant E i is cyclohexyl radical.

4. N-cyclohexyl-N-cyanoethyl-p-methoxybenzamide. 10 5.N-cyclohexyl-N-cyanoethyl-m-rnethoxybenzamide. 260-464; 424-304

